Comparison of responses of spontaneously active cells in the cerebellar Purkinje layer to parallel fibre stimulation in slice preparations and urethane-anaesthetised rats: effects of benzodiazepine receptor ligands.
1. GABA-mediated inhibitory responses were induced in spontaneously active Purkinje cells by parallel fibre stimulation in cerebellar slices or in urethane-anaesthetised rats. Effects of agonist and inverse agonist benzodiazepine (BDZ) receptor ligands were compared in the preparations. 2. Purkinje cells fired simple spikes at higher rates in slice preparations while complex spikes were seldom (in vivo) or never observed (slice). Cells fired more regularly in vivo resulting in the occurrence of rhythmic postinhibitory responses in the PSTH analysis in some preparations. 3. Single pulse stimulation of parallel fibres at just suprathreshold intensity induced inhibition of Purkinje cell activity in both preparations. At lower firing rates there was a marked increase in the duration of this response, which was more evident in vivo where more slowly firing cells were encountered. 4. BDZ receptor ligands modified inhibitory responses in slice preparations with only weak effects on the firing rates of the cells. These compounds predominately induced changes in firing rate in the anaesthetised rat with little evidence of direct modification of GABA-mediated synaptic transmission. 5. In a few experiments, following injection of the partial inverse agonists beta-CCE and beta-CCM, block of the inhibitory response was observed independent of changes in firing rate. Bidirectional efficacy of BDZ receptor ligand (agonists decrease firing and increase inhibitory response, inverse agonists increase firing and decrease inhibitory response) was demonstrated for modulation of inhibitory responses in slices and for changes in firing rate in vivo. The increased firing rate response in vivo was biphasic the magnitude of the later phase being correlated with efficacy of inverse agonists. 6. It is concluded that cerebellar slice preparations are more appropriate for studying direct effects of BDZ receptor ligands on GABA-mediated synaptic inhibition than in vivo preparations.
Gardner
C R
CR
Department of Physiology and Pharmacology, School of Biological Sciences, University of Southampton, England, UK.
Hussain
S
S
Pringle
A
A
Bagust
J
J
Walker
R J
RJ
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000758:Anesthesia; D018686:Anesthetics, Intravenous; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D004558:Electric Stimulation; D058785:GABA-A Receptor Agonists; D008024:Ligands; D008297:Male; D011689:Purkinje Cells / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D014520:Urethane; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000502:physiology
D018686:Anesthetics, Intravenous; D001381:Azepines; D058785:GABA-A Receptor Agonists; D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D014520:Urethane; D005680:gamma-Aminobutyric Acid; C043990:RU 32007; C056530:Ro 19-4603